Format

Send to

Choose Destination
Theranostics. 2019 May 9;9(10):2950-2966. doi: 10.7150/thno.29617. eCollection 2019.

CD137 promotes bone metastasis of breast cancer by enhancing the migration and osteoclast differentiation of monocytes/macrophages.

Jiang P1,2,3, Gao W4, Ma T4, Wang R4, Piao Y4, Dong X4, Wang P4, Zhang X2,5, Liu Y4,6, Su W4,6, Xiang R4,6, Zhang J1,2,3, Li N4,6.

Author information

1
Third Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
2
Tianjin's Clinical Research Center for Cancer, Tianjin, China.
3
Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China.
4
School of Medicine, Nankai University, 94 Weijin Road, Tianjin, China.
5
Department of Blood Transfusion, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
6
Tianjin Key Laboratory of Tumour Microenvironment and Neurovascular Regulation, Tianjin, China.

Abstract

Rationale: Bone is one of the most common metastatic sites of breast cancer. CD137 (4-1BB), a member of the tumor necrosis factor (TNF) receptor superfamily, is mainly expressed in activated leukocytes. Previous study demonstrates the effect of CD137-CD137L bidirectional signaling pathway on RANKL-mediated osteoclastogenesis. However, the role of CD137 in bone metastasis of breast cancer needs further study. Methods: Stable monocyte/macrophage cell lines with Cd137 overexpression and silencing were established. Western blot, real-time PCR, transwell and tartrate-resistant acid phosphatase staining were used to detect the regulatory effect of CD137 on migration and osteoclastogenesis of monocytes/macrophages in vitro. Spontaneous bone metastasis mouse model was established, bioluminescent images, immunohistochemistry and histology assay were performed to detect the function of CD137 in bone metastasis in vivo. Results: We found that CD137 promotes the migration of monocytes/macrophages to tumor microenvironment by upregulating the expression of Fra1. It also promoted the differentiation of monocytes/macrophages into osteoclasts at the same time, thus providing a favorable microenvironment for the colonization and growth of breast cancer cells in bone. Based on these findings, a novel F4/80-targeted liposomal nanoparticle encapsulating the anti-CD137 blocking antibody (NP-αCD137 Ab-F4/80) was synthesized. This nanoparticle could inhibit both bone and lung metastases of 4T1 breast cancer cells with high efficacy in vivo. In addition, it increased the therapeutic efficacy of Fra1 inhibitor on tumor metastasis. Conclusions: Taken together, these findings reveal the promotion effect of macrophage/monocyte CD137 on bone metastases and provide a promising therapeutic strategy for metastasis of breast cancer.

KEYWORDS:

Fra1; anti-CD137 antibody; bone metastasis; breast cancer; liposomal nanoparticles; metastatic niche.

Supplemental Content

Full text links

Icon for Ivyspring International Publisher Icon for PubMed Central
Loading ...
Support Center